Study May Lead to More Refined Approaches for Head and Neck Cancers

By targeting an enzyme that plays a key role in head and neck cancer cells, researchers at UCLA’s School of Dentistry were able to significantly slow the growth and spread of tumors in mice and improve the effectiveness of immunotherapy to which these types of cancers often become resistant.

Their findings, published online in the journal Molecular cell, could help researchers develop more sophisticated approaches to fight highly invasive squamous cell cancers of the head and neck, which primarily affect the mouth, nose and throat.

Immunotherapy, which is used as a clinical treatment for various cancers, harnesses the body’s natural defenses to fight disease. Yet some cancers, including squamous cell carcinoma of the head and neck, do not respond as well to therapy as others. The prognosis for these head and neck cancers is poor, with a high death rate at five years, and there is an urgent need for effective treatments.

The UCLA research team, led by eminent professor Dr. Cun-Yu Wang, chair of oral biology at the school of dentistry, demonstrated that by targeting a vulnerability in the cellular process of duplication and tumor immunity, they could affect the response of tumor cells to immunotherapy. .

The enzyme they focused on, KDM4A, is what’s called an epigenetic factor – a molecule that regulates gene expression, silencing certain genes in cells and turning on others. In squamous cell carcinoma of the head and neck, overexpression of KDM4A promotes gene expression associated with the replication and spread of cancer cells.

It is well known that tumor cells can spread undetected by the immune system and, left unattended, can metastasize to lymph nodes or other parts of the body. In this case, tumor cells that develop in the epithelial layer that lines the structures of the head and neck can develop into squamous cell carcinoma of the head and neck when left unchecked.

Cancer cell replication occurs through the abnormal spread and activation of cancer cell signaling pathways, and the researchers asked the question: If we can disrupt these processes and identify a vulnerability, can we change the response of the cancer cell? body to fighting cancer cells and its response to outside immunotherapy?

We know that the KDM4A gene plays a vital role in the replication and spread of cancer cells, so we focused our study on removing this gene to see if we would get an opposite response.. “

Dr Cun-Yu Wang, study correspondent author and member of the Jonsson Comprehensive Cancer Center, University of California – Los Angeles

By removing the KDM4A gene in their mouse models, the researchers found a noticeable decrease in squamous cell carcinoma and much less cancer metastasis to the lymph nodes – a precursor to the disease spreading throughout the body.

Surprisingly, they also found that the elimination of KDM4A also led to the recruitment and activation of anti-infective T cells in the body, which kill cancer cells and boost inherent tumor immunity.

They then set out to find out why squamous cell carcinoma cells had such a poor response to immunotherapy treatment. In another set of mouse models, they again eliminated KDM4A and introduced a PD-1 blockade, which signals immunotherapy drugs to attack cancer cells. The combination of immunotherapy and elimination of KDM4A further reduced the growth of squamous cell cancer and lymph node metastasis.

Next, the researchers tested whether a small molecule inhibitor of KDM4A could improve the effectiveness of immunotherapy based on the original PD-1 blockade. They found that the inhibitor also significantly helped kill cancer stem cells, which are associated with cancer relapse.

The results are promising for the development of more specific inhibitors of KDM4A and more effective anti-cancer immunotherapies.

“I am constantly impressed with Dr. Cun-Yu Wang and his team for breaking through barriers in our understanding of carcinogenic cellular processes,” said Dr. Paul Krebsbach, Dean and Professor in the Faculty of Dentistry at UCLA. “The results of this study have major implications for the development of more effective and life-saving cancer therapies.”